We seek to discover new, medically relevant mechanisms governing red blood cell formation (erythropoiesis). Recently identified small non-coding RNAs, termed microRNAs (miRs), profoundly influence normal development and stress responses in virtually all tissues. MiRs suppress protein synthesis by inhibiting the translation and stability of specific target mRNAs that are recognized via Watson-Crick base pairing. This proposal investigates the role of miRs 144 and 451, which are encoded on a single gene locus that is strongly induced during erythropoiesis. In zebrafish and mice, loss of miR-451 impairs erythropoiesis, sensitizes mature erythrocytes to destruction by oxidant stress and induces erythroid precursor apoptosis after acute anemia. Preliminary data indicate that miR-144/451 regulates iron uptake, survival, maturation, and mitochondrial energy metabolism during erythropoiesis through confirmed target mRNAs including Rab14, Myc, Ywhaz, and Cab39. We will investigate further the mechanisms through which miRs 144 and 451 control erythropoiesis at baseline, and during disease-related stresses including blood loss, iron deficiency, and unbalanced hemoglobin production (thalassemia). Our work should provide new insights into erythroid development and associated disorders including myeloproliferative syndromes and various anemias. Moreover, knowledge gained through our studies of erythropoiesis should be applicable to other biological processes where miR-451 is believed to function, including protection against myocardial stress, regulation of immune responses and as a tumor suppressor in numerous malignancies.